Migraine affects more than 6 million children and adolescents in the United States and the majority continue to experience migraines into adulthood. The annual economic impact of migraine in the U.S. is $36 billion (direct medical costs + lost productivity). Over 130,000 school days are missed every two weeks due to migraine. Yet, no prevention medication is FDA-approved for childhood migraine and pediatric clinical practice guidelines are consensus-based, not evidence-based. The central problem is the lack of placebo-controlled clinical trials and comparative effectiveness studies of prophylactic medication therapy. To address this problem, we propose the 'Amitriptyline and Topiramate in the Prevention of Childhood Migraine'Trial. This pivotal pediatric project will address three critical questions in one clinical trial. Collectively, the results will transform the knowledge base available to clinicians and provide vital evidence needed to change and optimize practice. Because amitriptyline (AMI) and topiramate (TPM) are commonly used by pediatric headache specialists, but currently lack the empirical data to be recommended as Class I evidence in the American Academy of Neurology practice parameters, the first two questions address the efficacy, tolerability, and safety of the two medications relative to placebo. The third question asks, for the first time with children, how these two medications compare to each other in terms of efficacy, tolerability, and safety. Our goal is to determine the first choice prevention medication therapy for pediatric migraine using a decision algorithm developed specifically for this project. We will conduct a 3-arm, randomized, double-blind, parallel group, placebo-controlled trial testing AMI and TPM with 675 children and adolescents between age 8 and 17 with migraine recruited from up to 40 sites across the United States. Participants will be randomized in a 2:2:1 fashion (AMI [N=270];TPM [N=270];Placebo [N=135]) and will receive prevention medication therapy or placebo for 24 weeks. The primary endpoint will be a >50% reduction in migraine frequency from baseline (measured by daily pain diary) during the final 4 weeks of this 24-week clinical trial. Key secondary endpoints will be migraine-related disability, tolerability, and safety. PUBLIC HEALTH RELEVANCE: This phase III trial will cost about $3 for every child in the United States who suffers from migraine. The results will be directly translated into clinical care decisions worldwide by practitioners who treat children with migraines (including pediatricians, family practitioners, neurologists, and headache medicine specialists). The project is of high priority for the fields of neurology and headache medicine, and most importantly, for the millions of children who need evidence-based options available to prevent this painful illness.